Catalyzed Intramolecular Michael Reaction of ... - ACS Publications

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The Journal of Organic Chemistry

FeCl3 Catalysed Intramolecular Michael Reaction of Styrenes for The Synthesis of Highly Substituted Indenes Dattatraya H. Dethe,* Ganesh M. Murhade and Sourav Ghosh [email protected] Department of Chemistry, Indian Institute of Technology Kanpur.

ABSTRACT: An intramolecular FeCl3 catalysed Michael addition reaction of styrene, a poor nucleophile, onto the α-β unsaturated ketones was developed for the synthesis of highly substituted indene derivatives. The method was further applied for the total synthesis of sesquiterpene natural product (±)jungianol and 1-epi-jungianol.

Michael addition reaction is a fundamental carbon-carbon bond forming reaction.1 Over the decades many variants of this reaction have been developed, intermolecular olefin-Michael addition reaction have been reported by various groups, in 1980 Snider and co-workers reported that a stoichiometric amount of a Lewis acid catalyzed the addition of alkenes to α,β-enones.2a Okamoto and Ohe described an acid-catalyzed addition of simple alkenes to β-silyl substituted enones (Scheme-1 eq.1).2b Recently, Luo et. al. reported an anionic ligand strategy to facilitate β-proton elimination by suppressing cationic olefin polymerization, thus enabling the β-vinylation of enones with a variety of simple alkenes (Scheme-1 eq.2).2c Although intermolecular Michael reaction is well studied, the analogous intramolecular Michael reaction of olefin (alkene/styrene double bond) has rarely been explored due to the low nucleophilicity

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Scheme 1: Olefin-Michael addition reaction. of olefin carbon, uncontrolled side reactions as well as polymerization reaction in case of styrene derivatives. Variety of naturally occurring molecules contain indene/indane as a basic unit (fig. 1).3 Indene derivatives have various applications in pharmaceuticals,4 material chemistry5 and also used as a ligand for transition metal complexes.6 Due to the various applications of indene derivatives in diverse area, it is always subject of extensive study in organic synthesis and many methods for their synthesis have

Fig1: Indane Based Natural Products.


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been reported.7 With our ongoing interest in the development of novel methods for the synthesis of indene derivatives and its application in natural product synthesis by C-C bond forming reactions,8a,b earlier we tried to construct the indene motif by intramolecular Michael reaction of styrene double bond onto α-β unsaturated ester, surprisingly reaction went in reverse direction than what we had planned and generated indene derivatives by intramolecular olefin cation cyclisation of cinnamates (Scheme 2).8a Scheme 2: Intramolecular Olefin-Cationic Cyclisation and Intramolecular Olefin-Michael Cyclisation.

Scheme 3. Synthesis of α-β Unsaturated Ketone 13a.



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Table 1. Optimization of Olefin-Michael Cyclisation Reaction.

Entry

Catalyst

Equvi.

Solvent

Temp.

Time

Yield %

1

FeCl3

2

CH2Cl2

rt

5 min.

C. R. M.

2

FeCl3

1

CH2Cl2

rt

5 min.

C. R. M.

3

FeCl3

0.5

CH2Cl2

rt

5 min.

13

4

FeCl3

0.25

CH2Cl2

rt

5 min.

29

5

FeCl3

0.1

CH2Cl2

rt

5 min.

53

6

FeCl3

0.05

CH2Cl2

rt

5 min.

45

7

Sc(OTf)3

0.1

CH2Cl2

rt

12 h

N. R.

8

BF3·OEt2

0.1

CH2Cl2

rt

15 min.

68

9

Sn(OTf)2

0.1

CH2Cl2

rt

35 min.

90

10

SnCl4

0.1

CH2Cl2

rt

40 min.

50

11

ZnCl2

0.5

CH2Cl2

rt

24 h

N. R

12

FeCl3.6H2O

0.1

CH2Cl2

rt

15 min.

99

13

FeCl3.6H2O

0.1

THF

rt

12 h

N. R.

14

FeCl3.6H2O

0.1

CH3CN

rt

12 h

70

15

FeCl3.6H2O

0.1

MeOH

rt

12 h

N. R.

16

AgOTf

0.1

CH2Cl2

rt

5h

N. R.

17

TiCl4

0.1

CH2Cl2

rt

5h

N. R

18

InCl3

0.1

CH2Cl2

rt

1h

79

19

TiCl3

0.1

CH2Cl2

rt

5h

N.R.

20

PTSA

0.5

CH2Cl2

rt

12 h

N. R.

21

BiCl3

0.1

CH2Cl2

rt

3h

70

22

Fe(OTf)3

0.2

CH2Cl2

rt

30 min.

70

23

Cu(OTf)2

0.1

CH2Cl2

rt

24 h

N.R.

24

AlCl3

0.2

CH2Cl2

rt

12 h

N. R.

25

Cu(OTf)2

0.5

DCE

80 °C

12 h

32

C.R.M. = Complex reaction mixture, N.R. = No reaction


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According to proposed mechanism for this reaction, Lewis acid activates the ester group of cinnamate to generate intermediate 6a, which undergoes intramolecular cyclization with olefin, forming intermediate 6b which on subsequent rearomatization furnishes indene derivative 7 (scheme 2, Eq. 1). After reporting the FeCl3 mediated intramolecular olefin-cation cyclisation of cinnamates, we were interested to extend this method for unsaturated ketones to see that whether reaction will follow the same path and generate the similar type of indene motif. To begin with, the desired α-β unsaturated ketone 13a was prepared from commercially available ethyl ortho-bromobenzoate 10. Treatment of 10 with MeMgI followed by dehydration under acidic conditions generated the styrene derivative 11.9a Compound 11 on treatment with n-BuLi followed by quenching with DMF generated the aldehyde 12a.9b Aldol reaction of aldehyde 12a with acetone in presence of NaOH in ethanol afforded the required ketone 13a in 94% yield. After having the ketone 13a in hand, it was treated with 2 equiv. FeCl3 in CH2Cl2 as a solvent at room temperature, the best condition found for the olefin-cation cyclisation of cinnamates,8a but unfortunately to our disappointment it resulted in complex reaction mixture and we couldn’t isolate any compound from this mixture (table 1, entry 1). Same result was obtained when 13a was treated with 1 equiv. of FeCl3 in CH2Cl2 as a solvent at room temperature (table 1, entry 2). Due to decomposition of starting material with stoichiometric amount of FeCl3, it was decided to decrease the catalyst loading and surprisingly, we observed that when 13a was treated with 50 mol% of FeCl3 it generated olefin Michael addition product 14a in low yield (13%), instead of olefin-cation cyclisation product as in case of cinnamates and yield of 14a was improved to 53% when catalyst loading was decreased to 10 mol%, further decrease in catalyst loading also decreased the yield of the product 14a (entry- 3, 4, 5 and 6, Table 1). We then screened different Lewis acids as shown in table 1 for this transformation. Different acid catalyst such as p-TSA, Sc(OTf)3, AgOTf, Cu(OTf)2, AlCl3, TiCl3, TiCl4 and ZnCl2 failed to generate any product and starting material 13a was recovered. SnCl4 generated required cyclised compound 14a in 50% yield. Sn(OTf)2, InCl3, BiCl3 and Fe(OTf)3 afforded 14a with improved yield compared to FeCl3 and SnCl4 (entry-9, 18, 21, 22, Table



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1). Cu(OTf)2 in DCE at 80 °C afforded the Michael addition product in poor yield (32%) (entry- 25, Table 1). To our delight, ketone 13a on treatment with catalytic amount of FeCl3.6H2O in CH2Cl2 as a solvent at room temperature for 15 min. generated indene derivative 14a in almost quantitative yield (entry-12, Table 1). It is worth mentioning that to effect this transformation only catalytic Scheme 4: Olefin-Michael Cyclisation for Synthesis of Indene Derivative.

Diastereoselectivities determined from 1H NMR of the crude reaction mixture.

amount (10 mol%) of FeCl3.6H2O was required, unlike in the case of cinnamates derivatives 6, which required 2 equivalents of FeCl3 for olefin-cationic cyclisation reaction (Scheme 2, eq. (1)). The reaction was also found to be highly dependent on the solvent used, coordinative polar solvents such as THF, CH3CN and MeOH either generated low yield or proved ineffective in promoting the cyclisation reacACS Paragon Plus Environment

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tion (entry-13, 14, 15, Table 1). The plausible reaction mechanism is depicted in scheme 2 (eq.2). Lewis acid activates the enone of compound 8, which on Michael reaction with styrene double bond generates intermediate 8b, subsequent deprotonation furnishes indene derivative. After establishing the reaction conditions, in order to expand the scope of reaction, several chalcone derivatives 13b-g were subjected to this standard reaction condition and all were converted smoothly into indene derivatives 14b-g with excellent yields. However in case of α-β unsaturated aldehyde 13h, indene derivative 14h was obtained in only 40% yield. Scheme 5. Olefin-Michael Cyclisation for Synthesis of Indene Derivatives from Keto-dienone.

we prepared ketone 13i-n and dienone 13s-u having the aromatic ring or electron donating group on aromatic ring, all these compounds smoothly furnished cyclised products 14i-n and 14s-u respectively with very good yields (Scheme 3 and 4). Compound 13o and 13p containing ethyl and phenyl on αposition of styrene converted into 14o and 14p with 96% and 97% yield respectively. Interestingly, 13q having α- substitution on enone converted into 14q with 96% yield and 13r having the β-substitution on enone furnished the compound 14r in 93% yield with 3:4 diastereomeric mixture (Scheme 3). Next we applied this method in the total synthesis of sesquiterpene jungianol 1, which was isolated by Bolhmann et. al. in 1977 from a South American plant, Jungia malvaefolia. Jungianol is a sesquiterpene natural product containing tetrasubstituted indene framework, having methyl and isobutene side chains on the 1 and 3 position of the indane five-member ring respectively.3a Initial stereo chemical assignments of side chains by isolation group was later revised by Hashmi et. al. unambiguously by first total synthesis of ACS Paragon Plus Environment


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jungianol 1 and its epimer 17.10 Prior to their synthesis Ho et. al. reported the total synthesis and revision of another isomeric natural product mutisianthol 2 in 19974e that differs only in the position of the phenolic hydroxyl group from jungianol 1. Although the biological activity of jungianol 1 is not known, its isomer mutisianthol 2 exhibits moderate antitumor activity.4k Our group also reported total synthesis of (±)-jungianol 1 and mutisianthol 2 using Prins-type and Nazarov cyclisation respectively.8c,b Scheme 6. Retro Synthetic Analysis of (±)-Jungianol (1).

Scheme 7. Total Synthesis of (±)-Jungianol (1) and 1-epi-jungianol (17).

Retrosynthetic analysis of 1 is shown in Scheme 6. (±)-Jungianol 1 could be obtained from indene derivative 15 by regio- and stereo selective hydrogenation of an endocyclic double bond followed by deprotection of phenolic hydroxyl group. Indene derivative 15 could be synthesized from previously prepared Michael product 14d (Scheme 3) through Grignard reaction followed by elimination of tertiary alcohol. Accordingly indene derivative 14d on reaction with MeMgI followed by elimination of resulting tertiary alcohol, furnished mixture of isomers 15 and 16 in 78% yield. Inseparable mixture of isomers 15 and 16 on treatment with catalytic amount of p-TSA in CH2Cl2 at room temperature completely ACS Paragon Plus Environment

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converted into olefin 15 by isomerisation of geminally disubstituted olefin to more stable trisubstituted double bond. After having the required olefin 15 in hand, it was subjected for the selective hydrogenation of benzylic endocyclic double bond using Li/liq NH3 at -78 °C in THF followed by deprotection of resultant methyl ether furnished mixture of jungianol 1 and its epimer 17, which were carefully separated by silica gel column chromatography. The spectral data of jungianol 1 and epi-jungianol 17 (IR, 1H, 13

C, and HRMS) was in complete agreement with those reported in literature.3a,10

In conclusion, after varying Michael acceptor from unsaturated ester/amide/acid to unsaturated ketone/aldehyde on ortho-position of styrene, exclusive intramolecular olefin-Michael cyclisation reaction occurred instead of intramolecular olefin-cationic cyclisation. Various substituted indene derivatives were prepared from ortho substituted unsaturated keto styrenes using FeCl3.6H2O catalysed intramolecular olefin-Michael reaction. Further this reaction was utilised for the total synthesis of jungianol 1 (30% overall yield), and its 1-epi-jungianol 17 (30% overall yield).

EXPERIMENTAL SECTION General Aspects. All reactions were carried out under a nitrogen atmosphere with dry solvents under anhydrous conditions, unless otherwise mentioned. All the chemicals were purchased commercially and used without further purification. Anhydrous THF and diethyl ether were distilled from sodium benzophenone, and dichloromethane was distilled from calcium hydride. Yields refer to chromatographically pure compounds, unless otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm silica gel plates (60F-254) using UV light as a visualizing agent and a panisaldehyde or ninhydrine stain, and heat as developing agents. Silica gel (particle size: 100−200 and 230−400 mesh) was used for flash column chromatography. Neat coumpounds were used for recording IR spectra. NMR spectra were recorded on either 400 (1H, 400 MHz;

13

C, 100 MHz) or 500 (1H, 500

MHz; 13C, 125 MHz). Mass spectrometric data were obtained using Q-Tof-ESI. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet ACS Paragon Plus Environment


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of doublet, ddd = doublet of a doublet of a doublet, dt = doublet of a triplet, td = triplet of a doublet, m = multiplet, br = broad Experimental Procedures. A) General procedure for Aldol reaction: A mixture of corresponding aldehyde (1 equiv.) and the corresponding ketone (1 equiv.) in anhydrous ethanol was stirred at room temperature for 5 min. Then NaOH (3 equiv.) was added. The reaction mixture was stirred at room temperature until aldehyde consumed (usually up to 3h). After that, HCl (10%) was added until pH 5 was obtained. Extracted with ethyl acetate (3 x 7 ml). The organic layer was washed with brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue on a silica gel column chromatography using EtOAc-hexane as eluent furnished unsaturated ketone. (E)-4-(2-(prop-1-en-2-yl)phenyl)but-3-en-2-one (13a). According to the general procedure A for aldol reaction, 2-(prop-1-en-2-yl)benzaldehyde (12a) (1 gm, 6.84 mmol), acetone (18a) (0.5 ml, 6.84 mmol), and NaOH (820 mg, 20 mmol), in ethanol (7 ml) were used to furnish the product 13a (1.2 gm, 94%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 2924, 2852, 1692, 1672, 1608, 1595, 1463, 1358, 1313, 1254, 1176, 981; 1H NMR (400 MHz, CDCl3) δ 2.10 (d, J = 0.91 Hz, 3H), 2.36 (s, 3H), 4.88 (s, 1H), 5.36 (s, 1H), 6.65 (d, J = 16.3 Hz, 1H), 7.26 - 7.33 (m, 2H), 7.33 - 7.43 (m, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 16.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 24.9, 27.3, 117.6, 126.6, 127.4, 127.9, 128.3, 130.0, 131.7, 142.6, 143.7, 145.1, 198.6; HRMS: m/z calcd for C13H15O [(M+H)+]: 187.1123; Found: 187.1125. (E)-1-(2-(prop-1-en-2-yl)phenyl)non-1-en-3-one (13b). According to the general procedure A for aldol reaction, reaction, 2-(prop-1-en-2-yl)benzaldehyde (12a) (45 mg, 0.31 mmol), octan-2-one (18b) (37 mg, 0.31 mmol), and NaOH (35 mg, 0.92 mmol), in ethanol (2 ml) were used to furnish the product 13b (66 mg, 86%) as a yellow oil. Rf = 0.30 (EtOAc-hexane 3:97); IR (neat): vmax/cm-1 2956, 2929, 1691, 1667, 1609, 1595, 1480, 1452, 1303, 1174, 1074; 1H NMR (400 MHz, CDCl3) δ 0.89 (d, J = 14.0 Hz, 3H), 1.32 (m, 6H), 1.63 - 1.72 (m, 2H), 2.09 (s, 3H), 2.64 (t, J = 7.5 Hz, 2H), 4.86 (s, 1H), 5.35 (s, 1H),


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6.64 (s, 1H), 7.26 - 7.39 (m, 3H), 7.62 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 15.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.0, 22.5, 24.5, 24.9, 29.0, 31.6, 40.6, 117.6, 126.5, 127.0, 127.3, 128.3, 129.8, 131.9, 141.5, 143.7, 145.1, 201.0; HRMS: m/z calcd for C18H25O [(M+H)+]: 257.1905; Found: 257.1904. (E)-1-phenyl-3-(2-(prop-1-en-2-yl)phenyl)prop-2-en-1-one (13c). According to the general procedure A for aldol reaction, 2-(prop-1-en-2-yl)benzaldehyde (12a) (50 mg, 0.34 mmol), acetophenone (18c) (41 mg, 0.34 mmol), and NaOH (41 mg, 1.03 mmol), in ethanol (2 ml) were used to furnish the product 13c (70 mg, 82%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 3:97); IR (neat): vmax/cm-1 3060, 1662, 1603, 1592, 1479, 1447, 1314, 1212,1016; 1H NMR (500 MHz, CDCl3) δ 2.10 (s, 3H), 4.90 (s, 1H), 5.35 (d, J = 1.7 Hz, 1 H), 7.27 - 7.41 (m, 3H), 7.46 - 7.53 (m, 3H), 7.55 - 7.62 (m, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.96 - 8.04 (m, 2H), 8.06 (d, J = 15.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 24.9, 117.7, 122.7, 126.8, 127.3, 128.4, 128.5, 128.6, 130.0, 132.3, 132.7, 138.2, 143.7, 143.9, 143.9, 145.5, 190.6; HRMS: m/z calcd for C18H17O [(M+H)+]: 249.1279; Found: 249.1272. (E)-4-(2-methoxy-3-methyl-6-(prop-1-en-2-yl)phenyl)but-3-en-2-one (13d). According to the general procedure A for aldol reaction, 2-methoxy-3-methyl-6-(prop-1-en-2-yl)benzaldehyde (12b) (1 gm, 5.26 mmol), acetone (18a) (0.385 ml, 5.26 mmol), and NaOH (630 mg, 15.77 mmol), in ethanol (7 ml) were used to furnish the product 13d (1.12 gm, 93%) as a yellow oil. Rf = 0.23 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2927, 1670, 1456, 1327, 1251, 1093, 1014; 1H NMR (400 MHz, CDCl3) δ 2.01 (s, 3H), 2.30 (s, 3H), 2.35 (s, 3H), 3.67 (s, 3H), 4.89 (s, 1H), 5.23 - 5.26 (m, 1H), 6.90 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 16.5 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 16.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 15.9, 24.6, 27.4, 59.9, 116.8, 124.4, 125.0, 130.5, 131.2, 132.2, 139.0, 144.6, 144.8, 157.8, 199.4; HRMS: m/z calcd for C15H19O2 [(M+H)+]: 231.1385; Found: 231.1380. (E)-1-(2-methoxy-3-methyl-6-(prop-1-en-2-yl)phenyl)non-1-en-3-one (13e). According to the general procedure A for aldol reaction, 2-methoxy-3-methyl-6-(prop-1-en-2-yl)benzaldehyde (12b) (45 mg, 0.23 mmol), octan-2-one (18b) (28 mg, 0.23 mmol), and NaOH (28 mg, 0.71 mmol), in ethanol (5 ml) were used to furnish the product 13e (52 mg, 89%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 5:95); IR



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(neat): vmax/cm-1 2929, 1690, 1664, 1607, 1591, 1475, 1302, 1218, 1022; 1H NMR (400 MHz, CDCl3) δ 0.86 - 0.93 (m, 3H), 1.28 - 1.38 (m, 6H), 1.62 - 1.68 (m, 2H), 1.98 - 2.03 (m, 3H), 2.30 (s, 3H), 2.57 2.64 (m, 2H), 3.67 (s, 3H), 4.89 (dd, J = 1.8, 1.0 Hz, 1H), 5.24 (t, J = 1.8 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 16.5 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 16.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.0, 15.9, 22.5, 24.5, 24.6, 29.0, 31.6, 41.1, 59.9, 116.8, 124.4, 125.3, 130.3, 130.4, 132.0, 137.8, 144.6, 144.8, 157.8, 201.7; HRMS: m/z calcd for C20H29O2 [(M+H)+]: 301.2168; Found: 301.2162. (E)-4-(2-methoxy-3,4-dimethyl-6-(prop-1-en-2-yl)phenyl)but-3-en-2-one (13f). According to the general procedure A for aldol reaction, 2-methoxy-3,4-dimethyl-6-(prop-1-en-2-yl)benzaldehyde (12c) (100 mg, 0.49 mmol), acetone (18a) (0.036 ml, 0.49 mmol), and NaOH (59 mg, 1.47 mmol), in ethanol (3 ml) were used to furnish the product 13f (112 mg, 94%) as a yellow oil. Rf = 0.2 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2927, 1667, 1591, 1446, 1357, 1314, 1251, 1093, 1014; 1H NMR (400 MHz, CDCl3) δ 1.93 - 2.06 (m, 3H), 2.21 (s, 3H), 2.27 (s, 3H), 2.35 (s, 3H), 3.65 (s, 3H), 4.85 - 4.92 (m, 1H), 5.15 5.32 (m, 1H), 6.82 (s, 1H), 7.00 (d, J = 16.7 Hz, 1H), 7.68 (d, J = 16.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 12.1, 20.3, 24.7, 27.4, 60.2, 116.6, 122.4, 126.0, 129.3, 130.4, 139.3, 140.4, 143.9, 145.0, 157.8, 199.6; HRMS: m/z calcd for C16H20NaO2 [(M+Na)+]: 267.1361; Found: 267.1369. (E)-4-(2-methoxy-3,4,5-trimethyl-6-(prop-1-en-2-yl)phenyl)but-3-en-2-one (13g). According to the general procedure A for aldol reaction, 2-methoxy-3,4,5-trimethyl-6-(prop-1-en-2-yl)benzaldehyde (12d) (90 mg, 0.41 mmol), acetone (18a) (0.03 ml, 0.26 mmol), and NaOH (102 mg, 0.26 mmol), in ethanol (3 ml) were used to furnish the product 13g (96 mg, 94%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2926, 1665, 1600, 1572, 1453, 1358, 1250, 1102; 1H NMR (500 MHz, CDCl3) δ 1.94 (s, 3H), 2.18 (s, 3H), 2.23 (s, 3H), 2.25 (s, 3H), 2.32 - 2.34 (m, 3H), 3.61 - 3.64 (m, 3H), 4.81 (s, 1H), 5.38 (d, J = 1.1 Hz, 1H), 7.08 (d, J = 16.6 Hz, 1H), 7.67 (d, J = 16.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.7, 16.8, 16.9, 25.0, 27.4, 59.9, 116.9, 121.9, 128.9, 129.3, 130.4, 139.6, 140.0, 143.6, 144.4, 155.9, 199.9; HRMS: m/z calcd for C17H23O2 [(M+H)+]: 259.1698; Found: 259.1690. ACS Paragon Plus Environment

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(E)-3-(2-methoxy-3-methyl-6-(prop-1-en-2-yl)phenyl)acrylaldehyde (13h). Step 1: Benzyl chloride (0.72 ml, 6.3 mmol) was added to a stirred solution of the LAH4 (48 mg, 1.26 mmol) in dry THF (4 ml) at 0 °C and stirred reaction mixture for 30 minute at same temperature then (E)-ethyl 3-(2-methoxy-3methyl-6-(prop-1-en-2-yl)phenyl)acrylate (19) (110 mg, 0.42 mmol) in THF (1 ml) was added to this reaction mixture and resultant reaction mixture was stirred for 3h. The reaction mixture was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. Evaporation of the solvent furnished the alcohol, which was used in the oxidation reaction without further purification. Step 2: To a solution of the crude alcohol obtained in above reaction in ethyl acetate (4 ml) was added IBX (208 mg, 0.84 mmol) and refluxed for 3 h. Aq. NaHCO3 was added to the reaction mixture and extracted with ethyl acetate (3 x 15 ml). The organic extract was washed with brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue on a silica gel column chromatography using EtOAc-hexane as eluent furnished aldehyde 13h (70 mg, 77%) as a yellow oil. Rf = 0.40 (EtOAc-hexane 15:85); IR (neat): vmax/cm-1 2934, 1681, 1616, 1593, 1477, 1303, 1216, 1121, 1017; 1H NMR (400 MHz, CDCl3) δ 2.02 (s, 3H), 2.31 (s, 3H), 3.68 (s, 3H), 4.91 (s, 1H), 5.27 (s, 1H), 6.92 (d, J = 7.8 Hz, 1H), 7.04 (dd, J = 16.3, 8.0 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 16.0 Hz, 1H), 9.66 (d, J = 7.8 Hz, 1H);

13

C

NMR (100 MHz, CDCl3) δ 15.9, 24.7, 59.9, 117.1, 124.5, 130.6, 132.7, 133.3, 144.5, 144.8, 148.7, 158.0, 195.5; HRMS: m/z calcd for C14H17O2 [(M+H)+]: 217.1229; Found: 217.1223. (E)-3-(2-methoxy-3-methyl-6-(prop-1-en-2-yl)phenyl)-1-phenylprop-2-en-1-one (13i). According to the general procedure A for aldol reaction, 2-methoxy-3-methyl-6-(prop-1-en-2-yl)benzaldehyde (12b) (63 mg, 0.33 mmol), acetophenone (18c) (40 mg, 0.33 mmol), and NaOH (40 mg, 1.00 mmol), in ethanol (3 ml) were used to furnish the product 13i (78 mg, 81%) as a yellow oil. Rf = 0.30 (EtOAc-hexane 15:85); IR (neat): vmax/cm-1 2923, 1612, 1491, 1448, 1254, 1216, 1180, 1156; 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 2.05 (s, 3H), 2.33 (s, 3H), 3.72 (s, 3H), 4.94 (s, 1H), 5.29 (s, 1H), 6.93 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 7.3 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.96 (d, J = 1.8



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Hz, 2H), 8.01 - 8.09 (m, 2H);

13

Page 14 of 33

C NMR (100 MHz, CDCl3) δ 15.9, 24.8, 60.0, 116.9, 124.4, 125.9,

126.0, 128.5, 128.6, 145.0, 130.5, 132.2, 132.7, 138.3, 140.0, 145.0, 145.0, 158.0, 190.9; HRMS: m/z calcd for C20H21O2 [(M+H)+]: 293.1542; Found: 293.1543. (E)-1-(3,5-dimethoxyphenyl)-3-(2-methoxy-3-methyl-6-(prop-1-en-2-yl)phenyl)prop-2-en-1-one

(13j).

According to the general procedure A for aldol reaction, 2-methoxy-3-methyl-6-(prop-1-en-2yl)benzaldehyde (12b) (70 mg, 0.37 mmol), 1-(3,5-dimethoxyphenyl)ethanone (18d) (66 mg, 0.37 mmol), and NaOH (44 mg, 1.10 mmol), in ethanol (3 ml) were used to furnish the product 13j (99 mg, 76%) as a yellow oil. Rf = 0.40 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 2937, 1663, 1589, 1425, 1456, 1351, 1310, 1205, 1156, 1042; 1H NMR (500 MHz, CDCl3) δ 2.04 (s, 3H), 2.32 (s, 3H), 3.71 (s, 3H), 3.86 (s, 6H), 4.86 - 5.02 (m, 1H), 5.19 - 5.36 (m, 1H), 6.62 - 6.70 (m, 1H), 6.92 (d, J = 7.7 Hz, 1H), 7.11 - 7.21 (m, 3H), 7.86 (d, J = 15.7 Hz, 1H), 7.96 (d, J = 16.0 Hz, 1H);

13

C NMR (100 MHz,

CDCl3) δ 15.9, 24.7, 55.5, 60.0, 105.1, 106.1, 106.3, 116.8, 124.5, 125.7, 126.1, 130.5, 132.2, 140.1, 140.3, 144.9, 145.1, 158.0, 160.8, 190.5; HRMS: m/z calcd for C22H24NaO4 [(M+Na)+]: 375.1572; Found: 375.1570. (E)-1-(3-methoxyphenyl)-3-(2-(prop-1-en-2-yl)phenyl)prop-2-en-1-one (13k). According to the general procedure A for aldol reaction, 2-(prop-1-en-2-yl)benzaldehyde (12a) (40 mg, 0.27 mmol), 1-(3methoxyphenyl) ethanone (18e) (41 mg, 0.27 mmol), and NaOH (32 mg, 0.82 mmol), in ethanol (2 ml) were used to furnish the product 13k (55 mg, 81%) as a yellow oil. Rf = 0.23 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2937, 1661, 1588, 1450, 1429, 1318, 1267, 1195, 1027; 1H NMR (500 MHz, CDCl3) δ 2.10 (s, 3H), 3.89 (s, 3H), 4.89 - 4.91 (m, 1H), 5.35 - 5.37 (m, 1H), 7.11 - 7.15 (m, 1H), 7.28 - 7.43 (m, 4H), 7.46 (d, J = 15.5 Hz, 1H), 7.55 (s, 1H), 7.59 - 7.62 (m, 1H), 7.74 (d, J = 7.7 Hz, 1H), 8.06 (d, J = 15.7 Hz, 1H);

13

C NMR (125 MHz, CDCl3) δ 24.9, 55.5, 112.8, 117.7, 119.2, 121.0, 122.8, 126.8,

127.3, 128.4, 130.0, 132.3, 139.6, 143.7, 144.0, 145.5, 159.9, 190.3; HRMS: m/z calcd for C19H19O2 [(M+H)+]: 279.1385; Found: 279.1388.


Page 15 of 33

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(E)-1-(2,5-dimethoxyphenyl)-3-(2-methoxy-3-methyl-6-(prop-1-en-2-yl)phenyl)prop-2-en-1-one

(13l).

According to the general procedure A for aldol reaction, 2-methoxy-3-methyl-6-(prop-1-en-2yl)benzaldehyde (12b) (80 mg, 0.42 mmol), 1-(2,5-dimethoxyphenyl)ethanone (18f) (76 mg, 0.42 mmol), and NaOH (50 mg, 1.26 mmol), in ethanol (3 ml) were used to furnish the product 13l (114 mg, 77%) as a yellow oil. Rf = 0.40 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 2937, 1654, 1581, 1493, 1463, 1412, 1301, 1276, 1222, 1042, 1022; 1H NMR (500 MHz, CDCl3) δ 2.02 (s, 3H), 2.30 (s, 3H), 3.70 (s, 3H), 3.80 (s, 3H), 3.84 (s, 3H), 4.91 (d, J = 0.9 Hz, 1H), 5.22 (d, J = 1.7 Hz, 1H), 6.87 - 6.93 (m, 2H), 7.01 (dd, J = 8.9, 3.1 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 7.19 (d, J = 3.1 Hz, 1H), 7.70 (d, J = 16.3 Hz, 1H), 7.81 (d, J = 16.0 Hz, 1H);

13

C NMR (100 MHz, CDCl3) δ 15.9, 24.6, 55.8, 56.3, 60.0,

113.1, 114.3, 116.6, 118.9, 124.4, 125.8, 129.8, 130.4, 130.7, 132.0, 138.9, 144.9, 145.1, 152.5, 153.5, 158.0, 193.3; HRMS: m/z calcd for C22H24NaO4 [(M+Na)+]: 375.1572; Found: 375.1573. (E)-1-(3,4-dimethoxyphenyl)-3-(2-methoxy-3-methyl-6-(prop-1-en-2-yl)phenyl)prop-2-en-1-one (13m). According to the general procedure A for aldol reaction, 2-methoxy-3-methyl-6-(prop-1-en-2yl)benzaldehyde (12b) (56 mg, 0.29 mmol), 1-(3,4-dimethoxyphenyl)ethanone (18g) (53 mg, 0.29 mmol), and NaOH (35 mg, 0.88 mmol), in ethanol (3 ml) were used to furnish the product 13m (79 mg, 76%) as a yellow oil. Rf = 0.20 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2935, 1655, 1594, 1580, 1514, 1463, 1417, 1304, 1265, 1162, 1023; 1H NMR (400 MHz, CDCl3) δ 2.05 (s, 3H), 2.33 (s, 3H), 3.71 (s, 3H), 3.97 (s, 6H), 4.95 (s, 1H), 5.28 (s, 1H), 6.92 - 6.94 (m, 2H), 7.15 (d, J = 7.7 Hz, 1H), 7.63 7.71 (m, 2H), 7.94 (s, 2H);13C NMR (100 MHz, CDCl3) δ 15.9, 24.7, 55.9, 56.0, 60.0, 110.0, 110.7, 116.7, 123.0, 124.5, 125.7, 125.8, 130.4, 131.4, 132.0, 139.1, 144.8, 145.2, 149.1, 153.1, 157.9, 189.1; HRMS: m/z calcd for C22H24NaO4 [(M+Na)+]: 375.1572; Found: 375.1571. (E)-1-(2-hydroxyphenyl)-3-(2-methoxy-3-methyl-6-(prop-1-en-2-yl)phenyl)prop-2-en-1-one (13n). According to the general procedure A for aldol reaction, 2-methoxy-3-methyl-6-(prop-1-en-2yl)benzaldehyde (12b) (100 mg, 0.53 mmol), 1-(2-hydroxyphenyl)ethanone (18h) (72 mg, 0.53mmol), and NaOH (63 mg, 1.58 mmol), in ethanol (3 ml) were used to furnish the product 13n (130 mg, 80%)



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Page 16 of 33

as a yellow oil. Rf = 0.30 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 3391, 2935, 1636, 1579, 1486, 1443, 1395, 1360, 1271, 1252, 1218, 1156, 1021; 1H NMR (400 MHz, CDCl3) δ 2.06 (s, 3H), 2.34 (s, 3H), 3.73 (s, 3H), 4.95 (s, 1H), 5.33 (s, 1H), 6.91 - 6.96 (m, 2H), 7.03 (dd, J = 8.4, 1.1 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.50 (ddd, J = 8.4, 7.1, 1.8 Hz, 1H), 7.87 (dd, J = 8.0, 1.6 Hz, 1H), 8.02 - 8.07 (m, 1H), 8.08 - 8.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 15.9, 24.8, 60.0, 117.1, 118.5, 118.8, 120.2, 124.2, 124.5, 125.3, 129.7, 130.6, 132.7, 136.2, 140.7, 144.9, 145.3, 158.2, 163.6, 194.7; HRMS: m/z calcd for C20H21O3 [(M+H)+]: 309.1491; Found: 309.1491. (E)-4-(2-(but-1-en-2-yl)phenyl)but-3-en-2-one(13o). According to the general procedure A for aldol reaction, 2-(but-1-en-2-yl)benzaldehyde (12c) (100 mg, 0.62 mmol), acetone (18a)

(36 mg, 0.62

mmol), and NaOH (75 mg, 1.87 mmol), in ethanol (3 ml) were used to furnish the product 13o (100 mg, 80%) as a yellow oil. Rf = 0.30 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2924, 1691, 1565, 1480, 1452, 1315, 1174; 1H NMR (400 MHz, CDCl3) δ 1.05 (t, J = 7.4 Hz, 3H), 2.33 - 2.36 (m, 3H), 2.36 2.45 (m, 2H), 4.88 (s, 1H), 5.33 (s, 1H), 6.64 (d, J = 16.3 Hz, 1H), 7.21 (dd, J = 7.5, 1.5 Hz, 1H), 7.30 (td, J = 7.5, 1.5 Hz, 1H), 7.36 (td, J = 7.4, 1.5 Hz, 1H), 7.63 (dd, J = 7.7, 1.2 Hz, 1H), 7.74 (d, J = 16.4 Hz, 1H);

13

C NMR (100 MHz, CDCl3) δ 12.4, 27.2, 31.3, 115.2, 126.4, 127.3, 127.8, 128.7, 129.8,

132.1, 142.6, 144.8, 149.7, 198.6; HRMS: m/z calcd for C14H17O [(M+H)+]: 201.1279; Found: 201.1286. (E)-4-(2-(1-phenylvinyl)phenyl)but-3-en-2-one (13p). According to the general procedure A for aldol reaction, 2-(1-phenylvinyl)benzaldehyde (12d) (104 mg, 0.5 mmol), acetone (18a) (29 mg, 0.5 mmol), and NaOH (60 mg, 1.5 mmol), in ethanol (3 ml) were used to furnish the product 13p (101 mg, 81%) as a yellow oil. Rf = 0.30 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 2950, 1695, 1586, 1472, 1215; 1H NMR (400 MHz, CDCl3) δ 2.08 (s, 3H), 5.24 (d, J = 1.2 Hz, 1H), 5.88 (d, J = 1.1 Hz, 1H), 6.50 (d, J = 16.4 Hz, 1H), 7.22 - 7.26 (m, 2H), 7.26 - 7.33 (m, 4H), 7.35 - 7.43 (m, 2H), 7.50 (d, J = 16.4 Hz, 1H), 7.62 - 7.68 (m, 1H);

13

C NMR (100 MHz, CDCl3) δ 26.4, 117.1, 126.4, 126.9, 128.0, 128.1, 128.2,


Page 17 of 33

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128.5, 130.1, 130.7, 133.1, 140.9, 142.6, 142.9, 147.9, 198.8; HRMS: m/z calcd for C18H17O [(M+H)+]: 249.1279; Found: 249.1280. (E)-4-(2-(prop-1-en-2-yl)phenyl)pent-3-en-2-one

(13q)

Step1:

A

solution

of

Diethyl

2-

oxopropanephosphonate (242 mg, 1.25 mmol) in THF (2 ml) was slowly added to a suspension of NaH (50 mg, 1.25 mmol) in THF (3 mL) at 0 °C during a period of 30 minutes. The mixture was stirred at room temperature and then became clear. 1-(2-(prop-1-en-2-yl)phenyl)ethanone (18c) (100 mg, 0.624 mmol) was added to the mixture at 0 °C, then stirred at room temperature for 30 hours. After confirmation of consumption of starting material, a solution of saturated aqueous NaHCO3 (3 mL) was added. THF was removed under reduced pressure, and the aqueous layer was extracted with dichloromethane (3 x 20 mL). The combined organic layer was washed with brine (2 mL) and dried with anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel furnish the product 13q (55 mg, 44%) as a yellow oil. Rf = 0.4 (EtOAchexane 10:90); IR (neat): vmax/cm-1 1655, 1589, 1465, 1314, 1265, 1262, 1023; 1H NMR (400 MHz, CDCl3) δ 2.03 (s, 3H), 2.24 (s, 3H), 2.41 (s, 3H), 4.98 (d, J = 1.4 Hz, 1H), 5.11 - 5.16 (m, 1H), 6.30 (d, J = 0.9 Hz, 1H), 7.13 - 7.17 (m, 1H), 7.23 - 7.25 (m, 1H), 7.27 - 7.34 (m, 2H);

13

C NMR (125 MHz,

CDCl3) δ 21.0, 23.9, 32.0, 116.4, 126.7, 127.0, 127.8, 127.9, 128.0, 128.7, 141.5, 142.1, 145.1, 157.1, 198.8; HRMS: m/z calcd for C14H17O [(M+H)+]: 201.1279; Found: 201.1281. (E)-2-methyl-1-phenyl-3-(2-(prop-1-en-2-yl)phenyl)prop-2-en-1-one (13r). According to the general procedure A for aldol reaction, 2-(prop-1-en-2-yl)benzaldehyde (12a) (50 mg, 0.34 mmol), propiophenone (18b) (46 mg, 0.34 mmol), and NaOH (41 mg, 1.03 mmol), in ethanol (3 ml) were used to furnish the product 13r (68 mg, 76%) as a yellow oil. Rf = 0.30 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 2924, 1692, 1660, 1595, 1368, 1224,; 1H NMR (400 MHz, CDCl3) δ 1.97 (s, 3H), 2.15 (d, J = 1.4 Hz, 3H), 4.84 (dd, J = 1.9, 1 Hz, 1H), 5.16 - 5.21 (m, 1H), 7.22 - 7.27 (m, 2H), 7.27 - 7.34 (m, 2H), 7.35 7.47 (m, 3H), 7.49 - 7.54 (m, 1H), 7.67 - 7.80 (m, 2H);

13

C NMR (100 MHz, CDCl3) δ 14.2, 24.2,



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Page 18 of 33

116.8, 126.7, 127.8, 128.1, 128.3, 129.3, 129.4, 131.5, 133.4, 136.8, 138.5, 142.6, 143.9, 144.3, 199.4; HRMS: m/z calcd for C19H19O [(M+H)+]: 263.1436; Found: 263.1439. (1E,4E)-1-(4-chlorophenyl)-5-(2-methoxy-3-methyl-6-(prop-1-en-2-yl)phenyl)penta-1,4-dien-3-one (13s). According to the general procedure A for aldol reaction, 4-chlorobenzaldehyde (20a) (70 mg, 0.30 mmol), ketone 13d (43 mg, 0.30 mmol), and NaOH (37 mg, 0.91 mmol), in ethanol (3 ml) were used to furnish the product 13s (95 mg, 89%) as a yellow oil. Rf = 0.30 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2927, 1656, 1612, 1490, 1406, 1318, 1218, 1090, 1012; 1H NMR (400 MHz, CDCl3) δ 2.03 2.04 (m, 3H), 2.32 (s, 3H), 3.70 (s, 3H), 4.92 - 4.93 (m, 1H), 5.28 (t, J = 1.8 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 7.01 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.36 - 7.40 (m, 2H), 7.43 (d, J = 16.0 Hz, 1H), 7.51 7.55 (m, J = 8.7 Hz, 2H), 7.64 (d, J = 16.0 Hz, 1H), 7.88 (d, J = 16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 15.9, 24.7, 60.0, 117.0, 124.4, 125.4, 126.5, 129.0, 129.2, 129.4, 130.5, 132.3, 133.3, 136.2, 139.0, 141.5, 144.8, 144.9, 157.9, 189.5; HRMS: m/z calcd for C22H22ClO2 [(M+H)+]: 353.1308; Found: 353.1309. (1E,4E)-1-(2-methoxy-3-methyl-6-(prop-1-en-2-yl)phenyl)-5-phenylpenta-1,4-dien-3-one (13t). According to the general procedure A for aldol reaction, benzaldehyde (20b) (90 mg, 0.40 mmol), ketone 13d (42 mg, 0.40 mmol), and NaOH (47 mg, 1.17 mmol), in ethanol (3 ml) were used to furnish the product 13t (98 mg, 79%) as a yellow oil. Rf = 0.29 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2931, 1652, 1616, 1475, 1444, 1394, 1332, 1218, 1098; 1H NMR (400 MHz, CDCl3) δ 2.04 (s, 3H), 2.33 (s, 3H), 3.71 (s, 3H), 4.94 (s, 1H), 5.29 (t, J = 1.4 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 16.0 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 5.0, 1.8 Hz, 3H), 7.46 (d, J = 16.0 Hz, 1H), 7.58 - 7.63 (m, 2H), 7.71 (d, J = 16.0 Hz, 1H), 7.88 (d, J = 16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 15.9, 24.7, 60.0, 116.9, 124.4, 125.5, 126.2, 128.3, 128.3, 128.9, 129.1, 130.4, 130.5, 132.2, 134.9, 138.8, 143.0, 144.9, 157.9, 189.8; HRMS: m/z calcd for C22H23O2 [(M+H)+]: 319.1698; Found: 319.1690. (1E,4E)-1-(2-methoxy-3-methyl-6-(prop-1-en-2-yl)phenyl)-5-p-tolylpenta-1,4-dien-3-one (13u). According to the general procedure A for aldol reaction, 4-methylbenzaldehyde (20c) (80 mg, 0.35 mmol), ke-


Page 19 of 33

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tone 13d (42 mg, 0.35 mmol), and NaOH (42 mg, 1 mmol), in ethanol (3 ml) were used to furnish the product 13u (92 mg, 77%) as a yellow oil. Rf = 0.30 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 2931, 1651, 1614, 1511, 1448, 1325, 1258, 1179, 1096, 1037; 1H NMR (400 MHz, CDCl3) δ 2.04 (s, 3H), 2.33 (s, 3H), 2.39 (s, 3H), 3.71 (s, 3H), 4.89 - 4.99 (m, 1H), 5.26 - 5.29 (m, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 16.0 Hz, 1H), 7.16 (d, J = 7.3 Hz, 1H), 7.19 - 7.25 (m, J = 8.2 Hz, 2H), 7.45 (d, J = 16.5 Hz, 1H), 7.48 - 7.54 (m, J = 8.2 Hz, 2H), 7.69 (d, J = 16.0 Hz, 1H), 7.87 (d, J = 16.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 15.9, 21.5, 24.7, 59.9, 116.9, 124.4, 125.3, 125.6, 125.9, 128.3, 129.2, 129.6, 130.4, 132.1, 132.1, 138.5, 140.9, 143.1, 144.8, 144.9, 157.9, 189.9; HRMS: m/z calcd for C23H24NaO2 [(M+Na)+]: 355.1674; Found: 355.1674. B) General procedure for the olefin-Michael cyclisation reaction: Under argon atmosphere to a magnetically stirred solution of keto in CH2Cl2 was added FeCl3.6H2O (10 mol %) and stirred for 15 to 30 min. When completion of the reaction was noticed by TLC, added saturated solution of NaHCO3 and resultant reaction mixture was extracted with CH2Cl2. The combined organic extract was washed with brine and dried over Na2SO4. Evaporation of solvent and purification of residue on a silica gel column using EtOAc-hexane as eluent, afforded cyclised product. 1-(3-methyl-1H-inden-1-yl)propan-2-one (14a). According to the general procedure of cyclization reaction, compound 13a (71 mg, 0.381 mmol) and FeCl3.6H2O (10.3 mg, 0.038 mmol), in CH2Cl2 (4 ml) were used to furnish the product 14a (70 mg, 99%) as a yellow oil. Rf = 0.29 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2920, 1716, 1463, 1359, 1155; 1H NMR (400 MHz, CDCl3) δ 2.13 (s, 3H), 2.18 (s, 3H), 2.52 (dd, J = 17.3, 8.6 Hz, 1H), 2.85 (dd, J = 17.4, 6.4 Hz, 1H), 3.83 - 3.93 (m, 1H), 6.17 (s, 1H), 7.15 - 7.24 (m, 1H), 7.27 - 7.33 (m, 2H), 7.35 (d, J = 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 12.9, 30.3, 43.9, 45.3, 119.1, 122.8, 124.9, 126.7, 133.3, 139.4, 145.4, 147.3, 207.7; HRMS: m/z calcd for C13H15O [(M+H)+]: 187.1123; Found: 187.1126. 1-(3-methyl-1H-inden-1-yl)octan-2-one (14b). According to the general procedure of cyclization reaction, compound 13b (36 mg, 0.140 mmol) and FeCl3.6H2O (3.8 mg, 0.014 mmol), in CH2Cl2 (3 ml)



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were used to furnish the product 14b (34 mg, 94%) as a yellow oil. Rf = 0.4 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2956, 2929, 2857, 1712, 1606, 1463, 1405, 1375, 1265, 1126, 1080; 1H NMR (400 MHz, CDCl3) δ 0.88 (s, 2H), 1.28 (br. s., 4H), 1.59 (m, 3H), 2.12 (s, 3H), 2.41 (t, J = 7.5 Hz, 2H), 2.49 (dd, J = 17.2, 8.5 Hz, 1H), 2.80 (dd, J = 17.2, 6.5 Hz, 1H), 3.87 - 3.91 (m, 1H), 6.16 (s, 1H), 7.15 - 7.22 (m, 1H), 7.27 - 7.35 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 12.9, 13.0, 14.0, 22.5, 23.8, 28.9, 29.7, 31.6, 43.2, 43.9, 44.3, 119.0, 122.8, 124.9, 126.6, 133.4, 139.3, 145.4, 147.5, 210.2; HRMS: m/z calcd for C18H25O [(M+H)+]: 257.1905; Found: 257.1903. 2-(3-methyl-1H-inden-1-yl)-1-phenylethanone (14c). According to the general procedure of cyclization reaction, compound 13c (36 mg, 0.145 mmol) and FeCl3.6H2O (3.9 mg, 0.014 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14c (34 mg, 94%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2926, 1684, 1597, 1448, 1356, 1276, 1180, 1075; 1H NMR (500 MHz, CDCl3) δ 2.14 (s, 3H), 3.05 (dd, J = 17.3, 8.7 Hz, 1H), 3.39 (dd, J = 17.3, 6.2 Hz, 1H), 4.09 (br. s., 1H), 6.26 (s, 1H), 7.20 (dt, J = 8.0, 4.0 Hz, 1H), 7.29 - 7.34 (m, 2H), 7.42 (d, J = 7.2 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H);

13

C NMR (125 MHz, CDCl3) δ 12.9, 40.6, 44.2,

119.1, 123.0, 124.9, 126.7, 128.1, 128.6, 133.2, 133.7, 136.9, 139.3, 145.5, 147.6, 199.1; HRMS: m/z calcd for C18H17O [(M+H)+]: 249.1279; Found: 249.1272. 1-(7-methoxy-3,6-dimethyl-1H-inden-1-yl)propan-2-one (14d). According to the general procedure of cyclization reaction, compound 13d (40 mg, 0.174 mmol) and FeCl3.6H2O (4.6 mg, 0.017 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14d (39 mg, 97%) as a yellow oil. Rf = 0.3 (EtOAchexane 5:95); IR (neat): vmax/cm-1 2927, 1715, 1577, 1477, 1448, 1416, 1359, 1254, 1162, 1025; 1H NMR (400 MHz, CDCl3) δ 2.08 (br. s., 3H), 2.17 (s, 3H), 2.23 - 2.28 (m, 1H), 2.31 (s, 3H), 3.39 (dd, J = 17.5, 4.3 Hz, 1H), 3.79 (s, 3H), 3.94 - 4.06 (m, 1H), 6.14 (br. s., 1H), 6.96 (d, J = 7.4 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 12.9, 15.8, 30.3, 42.7, 43.4, 59.8, 114.9, 127.8, 130.1, 132.9, 137.5, 139.1, 145.7, 154.5, 208.1; HRMS: m/z calcd for C15H19O2 [(M+H)+]: 231.1385; Found: 231.1380. ACS Paragon Plus Environment

Page 21 of 33

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1-(7-methoxy-3,6-dimethyl-1H-inden-1-yl)octan-2-one (14e). According to the general procedure of cyclization reaction, compound 13e (40 mg, 0.133 mmol) and FeCl3.6H2O (3.6 mg, 0.013 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14e (37 mg, 92%) as a yellow oil. Rf = 0.33 (EtOAchexane 10:90); IR (neat): vmax/cm-1 2927, 2856, 1714, 1476, 1416, 1243, 1121, 1243, 1121, 1020; 1H NMR (400 MHz, CDCl3) δ 0.86 - 0.91 (m, 3H), 1.27 - 1.35 (m, 6H), 1.59 - 1.64 (m, 2H), 2.08 (br. s., 3H), 2.23 (dd, J = 17.2, 10.4 Hz, 1H), 2.31 (s, 3H), 2.33 - 2.41 (m, 1H), 2.41 - 2.50 (m, 1H), 3.35 (dd, J = 17.4, 4.3 Hz, 1H), 3.79 (s, 3H), 3.97 - 4.05 (m, 1H), 6.13 (br. s., 1H), 6.96 (d, J = 7.2 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 12.9, 14.0, 15.8, 22.5, 23.8, 28.9, 31.6, 42.4, 42.7, 43.2, 59.8, 114.9, 127.7, 130.0, 133.0, 137.6, 138.9, 145.7, 154.5, 210.6; HRMS: m/z calcd for C20H28NaO2 [(M+Na)+]: 323.1987; Found: 323.1981. 1-(7-methoxy-3,5,6-trimethyl-1H-inden-1-yl)propan-2-one (14f). According to the general procedure of cyclization reaction, compound 13f (30 mg, 0.12 mmol) and FeCl3.6H2O (3.3 mg, 0.012 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14f (29 mg, 97%) as a yellow oil. Rf = 0.3 (EtOAchexane 10:90); IR (neat): vmax/cm-1 2927, 1715, 1475, 1458, 1426, 1244, 1025; 1H NMR (400 MHz, CDCl3) δ 2.07 (br. s., 3H), 2.16 (s, 3H), 2.18 - 2.22 (m, 3H), 2.25 (d, J = 7.1 Hz, 1H), 2.31 (s, 3H), 3.38 (dd, J = 17.4, 4.3 Hz, 1H), 3.76 (s, 3H), 3.92 - 4.01 (m, 1 H), 6.12 (br. s., 1H), 6.89 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 11.9, 12.9, 20.5, 30.3, 42.7, 43.5, 60.1, 116.7, 126.3, 132.9, 134.9, 137.4, 139.1, 144.7, 154.3, 208.3; HRMS: m/z calcd for C16H21O2 [(M+H)+]: 245.1542; Found: 245.1542. 1-(7-methoxy-3,4,5,6-tetramethyl-1H-inden-1-yl)propan-2-one (14g). According to the general procedure of cyclization reaction, compound 13g (35 mg, 0.135 mmol) and FeCl3.6H2O (3.66 mg, 0.013 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14g (33 mg, 94%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 2928, 1714, 1576, 1461, 1416, 1360, 1270, 1163, 1091, 1005; 1H NMR (400 MHz, CDCl3) δ 2.16 (s, 3H), 2.21 (s, 3H), 2.23 (s, 3H), 2.24 (br. s., 1H), 2.30 (s, 3H), 2.44 (s, 3H), 3.41 (dd, J = 17.4, 4.3 Hz, 1H), 3.72 (s, 3H), 3.88 (m, 1H), 6.11 (br. s., 1H); 13C NMR



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Page 22 of 33

(125 MHz, CDCl3) δ 12.7, 15.4, 16.1, 18.5, 30.3, 41.4, 43.8, 60.1, 126.2, 126.5, 134.9, 136.1, 136.3, 140.7, 141.7, 152.4, 208.5; HRMS: m/z calcd for C17H23O2 [(M+H)+]: 259.1698; Found: 259.1696. 2-(7-methoxy-3,6-dimethyl-1H-inden-1-yl)acetaldehyde (14h). According to the general procedure of cyclization reaction, compound 13h (30 mg, 0.138 mmol) and FeCl3.6H2O (3.7 mg, 0.014 mmol), in CH2Cl2 (2.5 ml) were used to furnish the product 14h (12 mg, 40%) as a yellow oil. Rf = 0.3 (EtOAchexane 5:95); IR (neat): vmax/cm-1 2928, 2855, 1722, 1479, 1453, 1416, 1257, 1213, 1174, 1021; 1H NMR (400 MHz, CDCl3) δ 2.10 (s, 3H), 2.32 (s, 3H), 2.49 - 2.57 (m, 1H), 3.21 (ddd, J = 17.2, 4.5, 1.8 Hz, 1H), 3.81 (s, 3H), 3.97 (td, J = 4.3, 1.8 Hz, 1H), 6.04 - 6.27 (m, 1H), 6.98 (d, J = 7.2 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 9.68 (t, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.0, 15.9, 41.7, 43.4, 59.8, 115.1, 128.0, 130.4, 132.0, 132.0, 137.0, 139.8, 202.0; HRMS: m/z calcd for C14H17O2 [(M+H)+]: 217.1229; Found: 217.1220. 2-(7-methoxy-3,6-dimethyl-1H-inden-1-yl)-1-phenylethanone (14i). According to the general procedure of cyclization reaction, compound 13i (40 mg, 0.136 mmol) and FeCl3.6H2O (3.7 mg, 0.014 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14i (37 mg, 92%) as a yellow oil. Rf = 0.25 (EtOAchexane 5:95); IR (neat): vmax/cm-1 2933, 1684, 1579, 1596, 1415, 1448, 1257, 1212, 1019; 1H NMR (400 MHz, CDCl3) δ 2.10 (s, 3H), 2.35 (s, 3H), 2.76 (dd, J = 17.6, 11.2 Hz, 1H), 3.84 (s, 3 H), 4.03 (dd, J = 17.4, 3.7 Hz, 1H), 4.21 (dt, J = 11.0, 1.8 Hz, 1H), 6.26 (t, J = 1.6 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.3 Hz, 1H), 7.44 - 7.49 (m, 2H), 7.54 - 7.59 (m, 1H), 7.98 - 8.02 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 12.9, 15.8, 38.7, 42.9, 59.9, 114.9, 127.7, 128.1, 128.5, 130.1, 133.0, 133.2, 136.9, 137.7, 139.0, 145.8, 154.6, 199.4; HRMS: m/z calcd for C20H21O2 [(M+H)+]: 293.1542; Found: 293.1541. 1-(3,5-dimethoxyphenyl)-2-(7-methoxy-3,6-dimethyl-1H-inden-1-yl)ethanone (14j). According to the general procedure of cyclization reaction, compound 13j (34 mg, 0.110 mmol) and FeCl3.6H2O (3.0 mg, 0.011 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14j (32 mg, 94%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2936, 1684, 1593, 1425, 1457, 1355, 1296, 1253, 1205,


Page 23 of 33

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1155, 1065; 1H NMR (400 MHz, CDCl3) δ 2.09 (br. s., 3H), 2.34 (s, 3H), 2.72 (dd, J = 17.4, 11.0 Hz, 1H), 3.82 (s, 6H), 3.83 (s, 3H), 3.97 (dd, J = 17.4, 3.7 Hz, 1H), 4.18 (dt, J = 11.1, 1.5 Hz, 1H), 6.22 (s, 1H), 6.65 (t, J = 2.3 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 7.09 - 7.14 (m, 2H), 7.16 (d, J = 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.0, 15.8, 38.9, 43.0, 55.6, 59.9, 105.6, 105.8, 114.9, 127.7, 130.1, 133.2, 137.6, 138.8, 139.0, 145.8, 154.6, 160.8, 199.1; HRMS: m/z calcd for C22H24NaO4 [(M+Na)+]: 375.1573; Found: 375.1573. 1-(3-methoxyphenyl)-2-(3-methyl-1H-inden-1-yl)ethanone (14k). According to the general procedure of cyclization reaction, compound 13k (55 mg, 0.201 mmol) and FeCl3.6H2O (5.4 mg, 0.02 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14k (52 mg, 93%) as a yellow oil. Rf = 0.3 (EtOAchexane 5:95); IR (neat): vmax/cm-1 2923, 1685, 1583, 1597, 1485, 1463, 1430, 1276, 1256, 1162, 1044, 1071; 1H NMR (400 MHz, CDCl3) δ 2.15 (s, 3H), 3.04 (dd, J = 17.3, 8.7 Hz, 1H), 3.38 (dd, J = 17.5, 6.0 Hz, 1H), 3.86 (s, 3H), 4.09 (br. s., 1H), 6.25 (s, 1H), 7.12 (dt, J = 8.3, 1.1 Hz, 1H), 7.21 (dt, J = 7.5, 3.8 Hz, 1H), 7.30 - 7.34 (m, 2H), 7.34 - 7.38 (m, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.50 - 7.55 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 12.9, 40.8, 44.2, 55.4, 112.2, 119.1, 119.7, 120.8, 123.0, 124.9, 126.7, 129.6, 133.7, 138.2, 139.3, 145.5, 147.6, 159.8, 198.8; HRMS: m/z calcd for C19H19O2 [(M+H)+]: 279.1385; Found: 279.1381. 1-(2,5-dimethoxyphenyl)-2-(7-methoxy-3,6-dimethyl-1H-inden-1-yl)ethanone (14l). According to the general procedure of cyclization reaction, compound 13l (44 mg, 0.124 mmol) and FeCl3.6H2O (3.4 mg, 0.012 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14l (40 mg, 91%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 2937, 1672, 1609, 1579, 1495, 1464, 1413, 1278, 1222, 1162, 1021; 1H NMR (400 MHz, CDCl3) δ 2.07 (s, 3H), 2.31 (s, 3H), 2.81 (dd, J = 18.32, 10.99 Hz, 1H), 3.78 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H), 3.94 (dd, J = 17.9, 3.7 Hz, 1H), 4.18 (ddt, J = 10.9, 3.7, 1.8 Hz, 1H), 6.22 (t, J = 1.8 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.98 - 7.04 (m, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 3.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 12.9, 15.9, 43.4, 43.7,



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Page 24 of 33

55.8, 55.9, 59.8, 113.0, 113.9, 114.7, 154.7, 119.9, 127.6, 128.4, 129.9, 133.7, 138.5, 146.0, 153.2, 153.3, 201.2; HRMS: m/z calcd for C22H24NaO4 [(M+Na)+]: 375.1573; Found: 375.1572. 1-(3,4-dimethoxyphenyl)-2-(7-methoxy-3,6-dimethyl-1H-inden-1-yl)ethanone (14m). According to the general procedure of cyclization reaction, compound 13m (39 mg, 0.11 mmol) and FeCl3.6H2O (3.0 mg, 0.011mmol), in CH2Cl2 (3 ml) were used to furnish the product 14m (38 mg, 97%) as a yellow oil. Rf = 0.4 (EtOAc-hexane 20:80); IR (neat): vmax/cm-1 2934, 1673, 1586, 1514, 1463, 1417, 1345, 1267, 1153, 1023; 1H NMR (500 MHz, CDCl3) δ 2.08 (t, J = 1.6 Hz, 3H), 2.34 (s, 3H), 2.73 (dd, J = 17.3, 11.31 Hz, 1H), 3.84 (s, 3H), 3.92 - 3.95 (m, 6H), 3.97 (d, J = 3.4 Hz, 1H), 6.14 - 6.30 (m, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 7.4 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 7.52 - 7.65 (m, 2H);

13

C NMR (100 MHz,

CDCl3) δ 13.0, 15.8, 38.2, 43.2, 56.0, 56.0, 59.9, 110.0, 110.1, 114.9, 122.8, 127.7, 130.1, 130.1, 133.4, 137.7, 138.9, 145.9, 148.9, 153.2, 154.6, 198.1; HRMS: m/z calcd for C22H25O4 [(M+H)+]: 353.1753; Found: 353.1758. 1-(2-hydroxyphenyl)-2-(7-methoxy-3,6-dimethyl-1H-inden-1-yl)ethanone (14n). According to the general procedure of cyclization reaction, compound 13n (50 mg, 0.162 mmol) and FeCl3.6H2O (4.2 mg, 0.016 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14n (47 mg, 94%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 3350, 1691, 1638, 1612, 1579, 1485, 1446, 1349, 1255, 1207, 1156, 1020; 1H NMR (400 MHz, CDCl3) δ 2.10 (s, 3H), 2.34 (s, 3H), 2.76 (dd, J = 17.4, 11.0 Hz, 1H), 3.84 (s, 3H), 4.06 (dd, J = 17.4, 3.7 Hz, 1H), 4.11 - 4.22 (m, 1H), 6.23 (t, J = 1.6 Hz, 1H), 6.86 (td, J = 7.7, 1.1 Hz, 1H), 6.97 - 7.04 (m, 2H), 7.18 (d, J = 7.8 Hz, 1 H), 7.45 - 7.50 (m, 1H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 12.42 (s, 1H);

13

C NMR (100 MHz, CDCl3) δ 13.0, 15.8, 38.5, 42.7, 59.9, 115.0,

118.4, 118.9, 119.4, 127.9, 130.1, 130.3, 132.7, 136.3, 137.3, 139.4, 145.7, 154.6, 162.4, 205.7; HRMS: m/z calcd for C20H21O3 [(M+H)+]: 309.1491; Found: 309.1488. 1-(3-ethyl-1H-inden-1-yl)propan-2-one (14o). According to the general procedure of cyclization reaction, compound 13o (25 mg, 0.125 mmol) and FeCl3.6H2O (3.37 mg, 0.0125 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14o (24 mg, 96%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 5:95); IR


Page 25 of 33

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(neat): vmax/cm-1 2956, 1712, 1609, 1465, 1265, 1126, 1180; 1H NMR (400 MHz, CDCl3) δ 1.26 - 1.28 (m, 3H), 2.18 (s, 3H), 2.46 - 2.58 (m, 3H), 2.86 (dd, J = 17.3, 6.2 Hz, 1H), 3.87 (tt, J = 6.3, 2.0 Hz, 1H), 6.17 (q, J = 1.7 Hz, 1H), 7.17 - 7.21 (m, 1H), 7.26 - 7.34 (m, 2H), 7.36 (dd, J = 7.4, 0.8 Hz, 1H); 13C NMR

(100

MHz,

CDCl3)

δ 12.2, 20.6, 30.3, 43.8, 45.4, 119.1, 122.9, 124.9, 126.6, 131.2, 144.8, 145.6, 147.6, 207.7; HRMS: m/z calcd for C14H17O [(M+H)+]: 201.1279; Found: 201.1279. 1-(3-phenyl-1H-inden-1-yl)propan-2-one(14p). According to the general procedure of cyclization reaction, compound 13p (42 mg, 0.17 mmol) and FeCl3.6H2O (4.6 mg, 0.017 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14p (41 mg, 97%) as a yellow oil. Rf = 0.24 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 2950, 1691, 1658, 1485, 1446, 1349, 1255, 1020; 1H NMR (500 MHz, CDCl3) δ 2.22 (s, 3H), 2.65 (dd, J = 17.2, 8.6 Hz, 1H), 2.97 (dd, J = 17.7, 6.3 Hz, 1H), 4.01 - 4.11 (m, 1H), 6.56 (d, J = 2.3 Hz, 1H), 7.24 - 7.28 (m, 1H), 7.30 - 7.35 (m, 1H), 7.35 - 7.40 (m, 1H), 7.42 - 7.47 (m, 3H), 7.52 7.61 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 30.3, 44.2, 45.2, 120.6, 123.3, 125.3, 126.8, 127.7, 127.8, 128.6, 135.3, 135.6, 143.2, 144.4, 147.8, 207.4; HRMS: m/z calcd for C18H17O [(M+H)+]: 249.1279; Found: 249.1285. 1-(1,3-dimethyl-1H-inden-1-yl)propan-2-one(14q) According to the general procedure of cyclization reaction, compound 13q (25 mg, 0.124 mmol) and FeCl3.6H2O (3.3 mg, 0.0124 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14q (24 mg, 96%) as a yellow oil. Rf = 0.33 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 2942, 1694, 1666, 1580, 1420, 1256, 1020; 1H NMR (400 MHz, CDCl3) δ 1.36 (s, 3 H), 1.90 (s, 3 H), 2.09 (d, J = 1.8 Hz, 3H), 2.58 (d, J = 14.6 Hz, 1H), 2.89 (d, J = 15.1 Hz, 1H), 6.25 (s, 1H), 7.19 - 7.26 (m, 2H), 7.26 - 7.31 (m, 1H), 7.31 - 7.37 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 12.8, 22.9, 31.1, 49.7, 51.3, 119.4, 121.3, 125.2, 126.9, 137.2, 138.9, 144.1, 151.9, 207.6; HRMS: m/z calcd for C19H19O [(M+H)+]: 263.1436; Found: 263.1435. 2-(3-methyl-1H-inden-1-yl)-1-phenylpropan-1-one(14r). According to the general procedure of cyclization reaction, compound 13r (30 mg, 0.11 mmol) and FeCl3.6H2O (3.0 mg, 0.0.011 mmol), in CH2Cl2 (3 ACS Paragon Plus Environment


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ml) were used to furnish the product 14r (28 mg, 93%) as a yellow oil. Rf = 0.4 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 2950, 2840, 1693, 1658, 1485, 1545, 1509, 1250, 1020; 1H NMR (400 MHz, CDCl3) δ 1.00 (d, J = 6.8 Hz, 2H), 1.21 (d, J = 6.8 Hz, 3H), 2.10 (t, J = 1.8 Hz, 3H), 2.15 - 2.17 (m, 2H), 3.60 - 3.66 (m, 1H), 3.72 - 3.97 (m, 3H), 6.08 (s, 1H), 6.23 (s, 1H), 7.11 - 7.22 (m, 2H), 7.26 - 7.31 (m, 4H), 7.31 - 7.36 (m, 1H), 7.42 - 7.51 (m, 5H), 7.52 - 7.63 (m, 2H), 7.93 - 7.97 (m, 2H), 7.99 - 8.04 (m, 2H);

13

C NMR (125 MHz, CDCl3) δ 12.9, 13.0, 13.9, 14.7, 42.3, 42.8, 50.4, 50.9, 119.0, 119.0,

122.8, 124.4, 124.6, 124.9, 126.7, 128.4, 128.4, 128.6, 128.7, 130.1, 131.1, 132.7, 132.9, 133.0, 134.8, 136.5, 139.5, 140.4, 145.4, 145.9, 146.3, 146.4, 203.4, 203.6; HRMS: m/z calcd for C19H19O [(M+H)+]: 263.1436; Found: 263.1442. (E)-4-(4-chlorophenyl)-1-(7-methoxy-3,6-dimethyl-1H-inden-1-yl)but-3-en-2-one (14s). According to the general procedure of cyclization reaction, compound 13s (40 mg, 0.113 mmol) and FeCl3.6H2O (3.0 mg, 0.011 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14s (39 mg, 98%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2928, 1691, 1665, 1612, 1490, 1349, 1244, 1198, 1122, 1088; 1H NMR (500 MHz, CDCl3) δ 2.09 (br. s., 3H), 2.33 (s, 3H), 2.52 (dd, J = 17.2, 10.9 Hz, 1H), 3.63 - 3.69 (m, 1H), 3.84 (s, 4H), 4.02 - 4.20 (m, 1H), 6.19 (br. s., 1H), 6.70 (d, J = 16.6 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 16.0 Hz, 1H);

13

C NMR (125 MHz, CDCl3) δ 13.0, 15.8, 40.6, 42.9, 59.9, 114.9, 126.8,

127.7, 129.2, 129.4, 130.1, 132.9, 136.3, 137.5, 139.1, 141.2, 141.2, 145.8, 154.5, 199.3; HRMS: m/z calcd for C22H21ClNaO2 [(M+Na)+]: 375.1128; Found: 375.1120. (E)-1-(7-methoxy-3,6-dimethyl-1H-inden-1-yl)-4-phenylbut-3-en-2-one (14t). According to the general procedure of cyclization reaction, compound 13t (44 mg, 0.138 mmol) and FeCl3.6H2O (3.7 mg, 0.014 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14t (42 mg, 95%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 10:90); IR (neat): vmax/cm-1 2927, 1661, 1609, 1449, 1250, 1198, 1017; 1H NMR (400 MHz, CDCl3) δ 2.09 (br. s., Hz, 3H), 2.34 (s, 3H), 2.52 (dd, J = 16.8, 10.9 Hz, 1H), 3.68 (dd, J = 17.0, 3.8 Hz, 1H), 3.85 (s, 3H), 4.07 - 4.16 (m, 1H), 6.18 - 6.25 (m, 1H), 6.75 (d, J = 16.3 Hz, 1H), 6.98 (d, J ACS Paragon Plus Environment

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= 7.7 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.36 - 7.43 (m, 3H), 7.50 - 7.60 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 13.0, 15.8, 40.4, 43.0, 59.9, 114.9, 126.4, 127.7, 128.2, 128.9, 130.1, 130.4, 133.1, 134.5, 137.6, 139.0, 142.8, 145.8, 154.5, 199.5; HRMS: m/z calcd for C22H23O2 [(M+H)+]: 319.1698; Found: 319.1691. (E)-1-(7-methoxy-3,6-dimethyl-1H-inden-1-yl)-4-p-tolylbut-3-en-2-one (14u). According to the general procedure of cyclization reaction, compound 13u (42 mg, 0.126 mmol) and FeCl3.6H2O (2.42 mg, 0.012 mmol), in CH2Cl2 (3 ml) were used to furnish the product 14u (40mg, 95%) as a yellow oil. Rf = 0.3 (EtOAc-hexane 5:95); IR (neat): vmax/cm-1 2922, 1662, 1603, 1512, 1476, 1415, 1349, 1245, 1199, 1093; 1H NMR (500 MHz, CDCl3) δ 2.09 (br. s., 3H), 2.33 (s, 3H), 2.38 (s, 3H), 2.47 - 2.55 (m, 1H), 3.67 (dd, J = 16.9, 3.7 Hz, 1H), 3.85 (s, 3H), 4.11 (dt, J = 10.9, 2.0 Hz, 1H), 6.21 (br. s., 1H), 6.71 (d, J = 16.6 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.18 - 7.22 (m, J = 8.0 Hz, 2H), 7.41 - 7.44 (m, J = 8.0 Hz, 2H), 7.53 (d, J = 16.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 13.0, 15.8, 21.5, 40.3, 43.0, 59.9, 114.9, 125.5, 127.7, 128.2, 129.7, 130.1, 131.7, 133.1, 137.6, 138.9, 141.0, 142.9, 145.8, 154.5, 199.6; HRMS: m/z calcd for C23H24NaO2 [(M+Na)+]: 355.1674; Found: 355.1677. 7-methoxy-3,6-dimethyl-1-(2-methylprop-1-enyl)-1H-indene (15). Step 1: To a magnetically stirred solution of methyl magnesium iodide [prepared from magnesium turnings (25 mg, 1.05 mmol), catalytic iodine and methyl iodide (0.09 ml, 139 mmol) in anhydrous diethyl ether], was added slowly to the ketone 13d (80 mg, 0.35 mmol) in anhydrous diethyl ether. The reaction mixture was stirred for 2 h at RT. It was then quenched with aq. NH4Cl solution, extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent furnished the crude tertiary alcohol, which was used in the elimination reaction without further purification. Step 2: To a magnetically stirred solution of crude tertiary alcohol in anhydrous THF (3 ml) at 0 °C triethyl amine (0.24ml, 1.73 mmol) was added and stirred for 5 minute then mesyl chloride (0.08 ml, 1.04 mmol) added slowly. Resultant mixture was allowed to warm to room temperature and reaction mixture was stirred for 6h. It was then quenched with water, extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent fur-



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nished the mixture of crude 15 and 16 eliminated product, was used directly for isomerisation reaction without further purification. Step 3: Under argon atmosphere, to a stirred solution of crude eliminated compound in CH2Cl2 catalytic amount of p-TSA (6 mg, 0.035 mmol) was added at 0 C and stirred for ο

30 min. at room temperature. The reaction progress was monitored by TLC analysis then reaction was quenched by sodium bisulphate. The reaction mixture was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude product was purified on silica gel column chromatography using EtOAchexane as eluent to furnish the 15 (64 mg, 81% (over 3 steps)) Rf = 0.6 (EtOAc-hexane 2:98) as a yellow oil. IR (neat): vmax/cm-1 2969, 2859, 1575, 1475, 1254, 1226; 1H NMR (500 MHz, CDCl3) δ 1.75 (s, 3H), 1.91 (s, 3H), 2.10 (s, 3H), 2.31 (s, 3H), 3.77 (s, 3H), 4.37 (d, J = 9.7 Hz, 1H), 4.71 (d, J = 8.0 Hz, 1H), 5.91 (s, 1H), 6.94 (d, J = 7.4 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 13.0, 15.9, 18.3, 25.9, 47.1, 59.8, 114.5, 121.6, 127.7, 129.9, 132.8, 133.5, 138.4, 138.6, 146.3, 154.7; HRMS: m/z calcd for C16H19O [(M-H)+ ]: 227.1436; Found: 227.1438. Jungianol, (1) and epi-Jungianol, (17). Step 1: To a 30 ml of anhydrous ammonia at -78 C, was added ο

(20 mg, 6.6 mmol) lithium metal. A solution of (80 mg, 0.22 mmol) of 15, in 4 ml THF was then added at the same temperature, followed by stirring for 10 min. Quenching with ammonium chloride was followed by evaporation of the ammonia gave a crude product which was used further reaction without purification. Step 2: Under argon atmosphere, NaH (440 mg, 11 mmol, 60% in mineral oil) was washed with anhydrous hexane (3 times). After a few minutes, anhydrous DMF (4 ml) was added. To this mixture, was slowly added a solution of EtSH (0.47 ml, 6.60 mmol) in anhydrous DMF (1 ml) at 0 °C and the resulting yellow solution was stirred for 20 min at RT. A solution of crude in anhydrous DMF (1 ml) was then added drop wise and the resulting mixture was stirred for 5h at 130 °C. It was becoming slightly brown. The mixture was cooled to RT and the saturated solution of NH4Cl was added. The mixture was extracted with Et2O then organic phase was washed with H2O, brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the resulting brown oil was purified by


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flash chromatography (EtOAc-hexanes, 3:97 as eluent) to give jungianol (1) (31 mg, 41%) as a yellow colour Solid. Rf = 0.3 (EtOAc-hexane 1:99) and epi-jungianol (18) (31 mg, 41%) as a yellow colour Solid, Rf = 0.3 (EtOAc-hexane 1:99); Jungianol (1) : IR (neat): vmax/cm-1 3380, 2910, 1582, 1480, 1443, 1271; 1H NMR (400 MHz, CDCl3) δ 1.20 (d, J = 7.2 Hz, 3H), 1.81 (d, J = 1.4 Hz, 3H), 1.88 (d, J = 1.4 Hz, 3H), 1.94 (ddd, J = 3.2, 7.6, 12.7 Hz, 1H), 2.0 (ddd, J = 8.1, 8.1, 12.7 Hz, 1H), 2.20 (s, 3H), 3.26 (m, J = 2.7, 7.2, 7.7, 3.2 Hz, 1H), 4.18 (dm, J = 10.4 Hz, 1H), 5.30 (dm, J = 10.4 Hz, 1H), 5.59 (s, 1 H), 6.68 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 15.3, 18.1, 21.5, 26.0, 38.6, 40.0, 42.0, 115.4, 122.4, 127.4, 129.0, 130.2, 135.0, 148.4, 151.4; HRMS: m/z calcd for C15H21O [(M+H)+]: 217.1592; Found: 217.1598. 1-epi-jungianol (17): IR (neat): vmax/cm-1 3390, 2920, 1572, 1475, 1453, 1263; 1H NMR (400 MHz, CDCl3) δ 1.30 (d, J = 6.8 Hz, 3H), 1.35 (ddd, J = 10.4, 10.4, 12.2 Hz, 1H), 1.83 (d, J = 0.91 Hz, 3H), 1.87 (d, J = 0.91 Hz, 3H), 2.19 (s, 3H), 2.19 (s, 3H), 3.06 (dm, J = 10.4 Hz, 1H), 4.00 (td, J = 7.2, 7.2, 10.4 Hz, 1H), 5.35 (dm, J = 10.0 Hz, 1H), 5.92 (s, 1H), 6.67 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 15.7, 18.7, 19.7, 26.4, 38.8, 41.5, 44.2, 115.1, 122.9, 128.1, 129.7, 130.3, 136.5, 148.2; HRMS: m/z calcd for C15H21O [(M+H)+]: 217.1592; Found: 217.1598.

ASSOCIATED CONTENT AUTHOR INFORMATION Corresponding Author E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT



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G.M. thanks CSIR, New Delhi, for the award of a research fellowship. Financial support from IIT Kanpur is gratefully acknowledged. Supporting Information Characterizations of all new compounds, proton and carbon NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org. REFERENCES (1) (a) Jha, S. C.; Joshi, N. N. Arkivoc 2002, vii, 167. (b) Bensa, D.; Constantieux, T.; Rodriguez, J. Synthesis 2004, 923. (c) Comelles, J.; Moreno-Mañas M.; Vallribera, A. Arkivoc 2005, ix, 207. (d) Ranu, B. C.; Banerjee, S. Org. Lett. 2005, 7, 3049. (e) Chi, Y.; Gellman, S. H. Org. Lett. 2005, 7, 4253. (f) Willis, M. C.; Chauhan J.; Whittinham, W. G. Org. Biomol. Chem. 2005, 3, 3094. (g) Okino, T.; Hoashi, Y.; Fukukawa, T.; Xu X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 7, 119. (h) Ooi, T.; Ohara, D.; Fukumoto K.; Maruoka, K. Org. Lett. 2005, 7, 3195. (i) Palomo, C.; Vera, S.; Mielgo A.; GómezBengoa, E. Angew. Chem. Int. Ed. 2006, 45, 5984. (j) Wu, F.; Li, H.; Hong R.; Deng, L. Angew. Chem. Int. Ed. 2006, 45, 947. (k) Hara, T.; Kanai, S.; Mori, K.; Mizugaki, T.; Ebitani, K.; Jitsukawa, K.; Kaneda, K. J. Org. Chem. 2006, 71, 7455. (l) Ding, R.; Katebzadeh, K.; Roman, L.; Bergquist, K.-E.; Lindström, U. M. J. Org. Chem. 2006, 71, 352. (m) Ebitani, K.; Motokura, K.; Mori, K.; Mizugaki, T.; Kaneda, K. J. Org. Chem. 2006, 71, 5440. (n) Reddy, K. R.; Kumar, N. S. Synlett 2006, 2246. (o) Varala, R.; Sreelatha N.; Adapa, S. R. Synlett 2006, 1549. (p) Smith III, A. B.; Atasoylu, O.; Beshore, D. C. Synlett 2009, 2643. (q) Azizi, N.; Baghi, R.; Ghafuri, H.; Boloutchian, M.; Hashemi, M. Synlett, 2010, 379. (r) Sarkar, D.; Bhattarai, R.; Headley, A. D.; Ni, B. Synthesis 2011, 1993. (s) Li, W.; Wu, W.; Yang, J.; Liang, X.; Ye, J. Synthesis 2011, 1085. (t) Sharma, D.; Bandna, A. K.; Shil, B.; Singh Das, P. Synlett 2012, 23, 1199. (u) Fernández, M.; Uria, U.; Orbe, L.; Vicario, J. L.; Reyes, E.; Carrillo, L. J. Org. Chem. 2014, 79, 230.


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